1. Field of the Invention
The invention relates to bacterial antibiotic resistance. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
2. Brief Summary of the Related Art
Bacterial antibiotic resistance has become one of the most important threats to modern health care. Cohen, Science 257:1051-1055 (1992) discloses that infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Neu, Science 257:1064-1073 (1992) discloses that the need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents rendering them quickly ineffective.
The present crisis has prompted various efforts to elucidate the mechanisms responsible for bacterial resistance. Coulton et al., Progress in Medicinal Chemistry 31:297-349 (1994) teaches that the widespread use of penicillins and cephalosporins has resulted in the emergence of xcex2-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the xcex2-lactam ring common to numerous presently used antibiotics. More recently, Dudley, Pharmacotherapy 15: 9S-14S (1995) has disclosed that resistance mediated by xcex2-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance.
Attempts to address this problem through the development of xcex2-lactamase inhibitors have had limited success. Sutherland, Trends Pharmacol. Sci. 12: 227-232 (1991) discusses the development of the first clinically useful xcex2-lactamase inhibitor, clavulanic acid, which is a metabolite of Streptomyces clavuligerus. Coulton et al (supra) discloses two semi-synthetic inhibitors, sulbactam and tazobactam, presently available. Coulton et al. (supra) also teaches that in combination with xcex2-lactamase-susceptible antibiotics, xcex2-lactamase inhibitors prevent antibiotic inactivation by xcex2-lactamase enzymes, thereby producing a synergistic effect against xcex2-lactamase producing bacteria.
Li et al., Bioorg. Med. Chem. 5 (9): 1783-1788 (1997), discloses that xcex2-lactamase enzymes are inhibited by phosphonate monoesters. Li et al. teaches that better inhibitory activity is achieved by compounds with amido side-chains, but that such compounds suffer the disadvantage of hydrolytic instability. Li et al. discloses that benzylsulfonamidomethyl phosphonate monoesters exhibit better hydrolytic stability, but also significantly weaker potency against xcex2-lactamase enzymes, than do the corresponding benzylamidomethyl phosphonate monoesters. Dryjanski and Pratt, Biochemistry 34:3569-3575 (1995) teaches that p-nitrophenyl [(dansylamido)methyl]phosphonate irreversibly inactivates the P99 xcex2-lactamase enzyme, and describes its use as a mechanistic probe for studying the interaction of ligands with a second binding site of the enzyme.
The availability of only a few xcex2-lactamase inhibitors, however, is insufficient to counter the constantly increasing diversity of xcex2-lactamases, for which a variety of novel and distinct inhibitors has become a necessity. There is, therefore, a need for the ability to identify new xcex2-lactamase inhibitors. The development of fully synthetic inhibitors would greatly facilitate meeting this need.
The invention provides novel xcex2-lactamase inhibitors, which are structurally unrelated to the natural product and semi-synthetic xcex2-lactamase inhibitors presently available, and which do not require a xcex2-lactam pharmacophore.
In a first aspect, therefore, the invention provides novel xcex2-lactamase inhibitors. In one embodiment of the invention, the novel xcex2-lactamase inhibitor is a compound of Formula (I): 
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
R4 is selected from the group consisting of OH, F, SR7, and N(R7)2; and
R5 is selected from the group consisting of F, OR6, SR7, and N(R7)2,
where R6 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteraryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
provided that R4 and R5 are not both F, and further provided that R1 is not 5-dimethylamino-1-naphthyl when R2 and R3 are both H, R4 is OH, and R5 is 4-nitrophenoxy.
In another embodiment, the novel xcex2-lactamase inhibitor is a compound of Formula (I): 
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted;
R4 is OR8, where R8 is selected from the group consisting of phenyl substituted with at least one chloro, nitro, or fluoro substituent; heteroaryl; and substituted heteroaryl; and
R5 is OR6, where R6 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteraryl portion of any such group may be optionally substituted.
In yet another embodiment, the novel xcex2-lactamase inhibitor is a compound of Formula (II): 
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
Y is O, NR7, or S;
R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
R4 and R5 are independently selected from the group consisting of OH, F, SR7, N(R7)2, OR6,
where R6 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
provided that R4 and R5 are not both F or both OH.
In a second aspect, the invention provides pharmaceutical compositions comprising a compound of Formula (I) or Formula (II), or a pro-drug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
In a third aspect, the invention provides methods for inhibiting bacterial growth, such methods comprising administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue,: or organism, a xcex2-lactamase inhibitor of Formula (I) or Formula (II).